DAPA RESIST: DAPAgliflozin Versus Thiazide Diuretic in Patients With Heart Failure and Diuretic RESISTance
Study Details
Study Description
Brief Summary
To assess the effect of dapagliflozin compared with metolazone, added to furosemide, on diuresis and decongestion in hospitalised heart failure patients with diuretic resistance, and renal impairment. The primary analysis will be in patients with HFrEF but patients with HFpEF will also be recruited in an ancillary study and included in supplementary analyses.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
The investigators aim to assess whether SGLT2i (in addition to IV loop diuretic) results in greater diuresis and decongestion compared to the standard practice of treatment with the thiazide-like diuretic metolazone (in addition to IV loop diuretic) in patients hospitalised for heart failure, with both renal impairment and diuretic resistance. Dapagliflozin has received National Institute for Health and Care Excellence (NICE) approval as an add-on option to optimised standard care in patients with HFrEF. The investigators primary focus is patients with HFrEF as it is in ambulatory patients with this phenotype that SGLT2 inhibition has already been shown to reduce morbidity and mortality (DAPA-HF).However, the investigators will also enrol patients with HFpEF in an ancillary study as they present the same management challenges as patients with HFrEF and the study hypothesis and aims are as clinically relevant in HFpEF as in HFrEF. HFpEF patients in the ancillary study will undergo the same protocol as the main study. One recent trial demonstrating benefit of a SGLT1/2 inhibitor, the Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF), included patients with both HFrEF and HFpEF hospitalised with worsening heart failure (NCT03521934). This trial demonstrated similar efficacy of sotagliflozin on cardiovascular death and worsening heart failure in patients with a LVEF <50% and ≥50%.There are other large trials currently underway specifically with SGLT2i in ambulatory patients with HFpEF underway. These trials are either fully recruited, or close to full enrolment. Both already have extensive follow-up of several thousand patients and are due to complete follow up in the next 1-2 years (EMPEROR-Preserved and DELIVER). Therefore, the findings will be contemporaneous and complementary to the results of those trials.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: SGLT2i Sodium-glucose Co-transporter-2 inhibitors |
Drug: Dapagliflozin 10 MG Oral Tablet
Dapagliflozin 10mg once daily
Other Names:
|
| Experimental: Thiazide Thiazide or thiazide like diuretic |
Drug: Metolazone Tablets
Metolazone 5MG or 10MG once daily
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Diuretic effect [from randomisation to 48 hours]
Diuretic effect, as assessed by mean change in weight
- Diuretic effect [from randomisation to 72 hours]
Diuretic effect, as assessed by mean change in weight
- Diuretic effect [from randomisation to 96 hours]
Diuretic effect, as assessed by mean change in weight
Secondary Outcome Measures
- Change in congestion measured by ultrasound [from randomisation to 48 hours]
Change in congestion, assessed using lung ultrasound as a measure of the sum of B-lines across 8 zones
- Change in congestion measured by ultrasound [from randomisation to 72 hours]
Change in congestion, assessed using lung ultrasound as a measure of the sum of B-lines across 8 zones
- Change in congestion measured by ultrasound [from randomisation to 96 hours]
Change in congestion, assessed using lung ultrasound as a measure of the sum of B-lines across 8 zones
- Change in weight (as a measure of loop diuretic efficiency) [from randomisation to 48 hours]
Loop diuretic efficiency will be defined as weight loss in kilograms divided by furosemide equivalents in milligrams.
- Change in weight (as a measure of loop diuretic efficiency) [from randomisation to 72 hours]
Loop diuretic efficiency will be defined as weight loss in kilograms divided by furosemide equivalents in milligrams.
- Change in weight (as a measure of loop diuretic efficiency) [from randomisation to 96 hours]
Loop diuretic efficiency will be defined as weight loss in kilograms divided by furosemide equivalents in milligrams.
Other Outcome Measures
- Change in urinary spot sodium [from randomisation to 48 hours]
change in urinary spot urine measured in mmol/L
- Change in urinary spot sodium [from randomisation to 72 hours]
change in urinary spot urine measured in mmol/L
- Change in urinary spot sodium [from randomisation to 96 hours]
change in urinary spot urine measured in mmol/L
- Change in NT-proBNP [from randomisation to 48 hours]
measured in pg/ml
- Change in NT-proBNP [from randomisation to 72 hours]
measured in pg/ml
- Change in NT-proBNP [from randomisation to 96 hours]
measured in pg/ml
- Change in serum uric acid [from randomisation to 48 hours]
measured in umol/L
- Change in serum uric acid [from randomisation to 72 hours]
measured in umol/L
- Change in serum uric acid [from randomisation to 96 hours]
measured in umol/L
- Total net fluid loss [from randomisation to 48 hours]
difference between fluid intake and output measured in ml
- Total net fluid loss [from randomisation to 72 hours]
difference between fluid intake and output measured in ml
- Total net fluid loss [from randomisation to 96 hours]
difference between fluid intake and output measured in ml
- Change in dyspnoea [from randomisation to 48 hours]
Change in dyspnoea (breathlessness) measured using a 7 point Likert scale (1= strong positive to 7 = strong negative) and a 11-point Dyspnoea Numerical Rating scale (0= not breathless at all to 10=breathlessness as bad as you can imagine)
- Change in dyspnoea [from randomisation to 72 hours]
Change in dyspnoea (breathlessness) measured using a 7 point Likert scale (1= strong positive to 7 = strong negative) and a 11-point Dyspnoea Numerical Rating scale (0= not breathless at all to 10=breathlessness as bad as you can imagine)
- Change in dyspnoea [from randomisation to 96 hours]
Change in dyspnoea (breathlessness) measured using a 7 point Likert scale (1= strong positive to 7 = strong negative) and a 11-point Dyspnoea Numerical Rating scale (0= not breathless at all to 10=breathlessness as bad as you can imagine)
- Patient global assessment [from randomisation to 48 hours]
Change in patients perception of their own health measured using a 7 point Likert scale (1= strong positive to 7 = strong negative)
- Patient global assessment [from randomisation to 72 hours]
Change in patients perception of their own health measured using a 7 point Likert scale (1= strong positive to 7 = strong negative)
- Patient global assessment [from randomisation to 96 hours]
Change in patients perception of their own health measured using a 7 point Likert scale (1= strong positive to 7 = strong negative)
- Time from randomisation to discharge [through study completion, an average of 5 days]
Time from randomisation to discharge measured in hours
- In-hospital mortality [through study completion, an average of 5 days]
Number of patients who died in hospital
- Rate of heart failure re-hospitalisation or death [through study completion, an average of 5 days]
Number of patients who are re-admitted to hospital after initial discharge
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male or female ≥18 years of age
-
Informed consent
-
Primary reason for admission to hospital is worsening HF meeting the European Society of Cardiology (ESC) definition.14
-
Diuretic Resistance as defined as: Lack of weight loss or absence of a negative fluid balance (as defined above) over the preceding 24 hours despite treatment with high dose IV loop diuretic (equivalent of ≥160mg IV furosemide in 24 hours)
-
Plasma BNP ≥ 100 pg/mL or plasma NT-proBNP ≥ 400 pg/mL in current hospital admission
-
eGFR <60 ml/min/1.73m2 required within 24 hours before randomisation
-
Ongoing clinical evidence of congestion: pitting peripheral oedema and/or ascites and/or elevated jugular venous pressure, and/or radiographic or ultrasonic evidence of pulmonary congestion
-
Expected hospital length of stay >3 days
Exclusion Criteria:
-
Inability to give informed consent e.g. due to significant cognitive impairment
-
Intravascular volume depletion based on investigator's clinical assessment
-
eGFR <20 mL/min/1.73 m2
-
Alternative explanation for worsening renal function such as obstructive nephropathy, contrast induced nephropathy, or acute tubular necrosis
-
Enrollment in another randomised clinical trial involving medical or device-based interventions (co-enrolment in observational studies is permitted)
-
Women of child-bearing potential
-
History of allergy to SGLT2i or thiazide or thiazide-like diuretics or any of the excipients
-
Hypertrophic obstructive cardiomyopathy (HOCM) or significant valvular disease in whom surgical or percutaneous repair or replacement may be considered.
-
SGLT2i, thiazide or thiazide-like diuretics administration in the previous 48 hours prior to randomisation
-
Active genital tract infections
-
Anyone who, in the investigators' opinion, is not suitable to participate in the trial for other reasons
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Glasgow Royal Infirmary | Glasgow | Strathclyde | United Kingdom | G4 0SF |
| 2 | Queen Elizabeth University Hospital | Glasgow | Strathclyde | United Kingdom | G51 4TF |
Sponsors and Collaborators
- NHS Greater Glasgow and Clyde
- University of Glasgow
Investigators
- Study Chair: John McMurray, MBChB, University of Glasgow and NHS Greater Glasgow and Clyde
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- GN19CA407